JACC: HEART FAILURE

VOL. 3, NO. 3, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 2213-1779/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jchf.2014.09.009

CLINICAL RESEARCH

Improvement in Cardiac Energetics by Perhexiline in Heart Failure Due to Dilated Cardiomyopathy Roger M. Beadle, PHD,* Lynne K. Williams, PHD,y Michael Kuehl, MD,z Sarah Bowater, MD,z Khalid Abozguia, PHD,z Francisco Leyva, MD,z Zaheer Yousef, MD,x Anton J.M. Wagenmakers, PHD,k Frank Thies, PHD,* John Horowitz, MD,{ Michael P. Frenneaux, MD*

ABSTRACT OBJECTIVES The aim of this study was to determine whether short-term treatment with perhexiline improves cardiac energetics, left ventricular function, and symptoms of heart failure by altering cardiac substrate utilization. BACKGROUND Perhexiline improves exercise capacity and left ventricular ejection fraction (LVEF) in patients with heart failure (HF). 31P cardiac magnetic resonance spectroscopy can be used to quantify the myocardial phosphocreatine/ adenosine triphosphate ratio. Because improvement of HF syndrome can improve cardiac energetics secondarily, we investigated the effects of short-term perhexiline therapy. METHODS Patients with systolic HF of nonischemic etiology (n ¼ 50, 62  1.8 years of age, New York Heart Association functional class II to IV, LVEF: 27.0  1.44%) were randomized to receive perhexiline 200 mg or placebo for 1 month in a double-blind fashion. Clinical assessment, echocardiography, and

31

P cardiac magnetic resonance spectroscopy were

performed at baseline and after 1 month. A substudy of 22 patients also underwent cross-heart blood sampling at completion of the study to quantify metabolite utilization. RESULTS Perhexiline therapy was associated with a 30% increase in the phosphocreatine/adenosine triphosphate ratio (from 1.16  0.39 to 1.51  0.51; p < 0.001) versus a 3% decrease with placebo (from 1.36  0.31 to 1.34  0.31; p ¼ 0.37). Perhexiline therapy also led to an improvement in New York Heart Association functional class compared with placebo (p ¼ 0.036). Short-term perhexiline therapy did not change LVEF. Cross-heart measures of cardiac substrate uptake and respiratory exchange ratio (which reflects the ratio of substrates used) did not differ between patients who received perhexiline versus placebo. CONCLUSIONS Perhexiline improves cardiac energetics and symptom status with no evidence of altered cardiac substrate utilization. No change in LVEF is seen at this early stage. (Metabolic Manipulation in Chronic Heart Failure; NCT00841139) (J Am Coll Cardiol HF 2015;3:202–11) © 2015 by the American College of Cardiology Foundation.

From the *School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland; yDepartment of Cardiology, Toronto General Hospital, Toronto, Ontario, Canada; zDepartment of Cardiovascular Medicine, University of Birmingham, Birmingham, England; xDepartment of Cardiology, University Hospital of Wales, Cardiff, Wales; kResearch Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, England; and the {Department of Cardiology and Pharmacology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia. Supported by the British Heart Foundation (PG/06/105) and sponsored by the University Hospitals Birmingham NHS Foundation Trust. Dr. Leyva has served as a consultant for and received research support from Medtronic, St. Jude Medical, Boston Scientific, and Sorin. Dr. Frenneaux is an inventor who holds method of use patents for perhexiline in heart muscle diseases; and has served as a consultant for and received research support from Medtronic, St. Jude Medical, Boston Scientific, and Sorin. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 2, 2014; revised manuscript received September 5, 2014, accepted September 19, 2014.

Beadle et al.

JACC: HEART FAILURE VOL. 3, NO. 3, 2015 MARCH 2015:202–11

D

espite recent advances in treatment, heart

with HF by altering cardiac substrate utiliza-

ABBREVIATIONS

failure (HF) has devastating effects on

tion. To assess whether these changes occur

AND ACRONYMS

survival (1) and quality of life (2). Pharma-

early and are by inference directly respon-

cological therapy consists of diuretics and neurohor-

sible for the subsequent improvement in

monal modulating agents. It is well established that

cardiac function, we used a short-term (1-

energy deficiency contributes to the syndrome of HF

month) regimen of perhexiline that typically

(3), and this has been proposed as a therapeutic

resulted in plasma perhexiline levels in the

target.

low therapeutic range for approximately 2

In previous phase 2 studies, beneficial effects of perhexiline have been observed in refractory angina (4), HF (5), and hypertrophic cardiomyopathy (6).

weeks.

ATP = adenosine triphosphate CRLB = Cramer-Rao lower bound

HF = heart failure LVEF = left ventricular ejection fraction

MLWHFQ = Minnesota Living With Heart Failure

METHODS

Questionnaire

This is subject to variable metabolism by P4502D6,

NEFA = nonesterified fatty

of which there are several polymorphic variants.

STUDY DESIGN. This randomized, double-

Sustained high plasma levels may lead to hepatotox-

blind,

icity and neurotoxicity due to phospholipid accu-

study explored the effects of perhexiline

mulation in these tissues. It has been shown that

over 1 month (mean: 32 days; range: 29 to

NYHA = New York Heart

toxicity is avoided by plasma monitoring with dose

35 days) in patients with symptomatic, non-

Association

titration (7).

ischemic cardiomyopathy. All participants

placebo-controlled,

parallel-group

provided written informed consent, and SEE PAGE 212

research was performed in accordance with

acids

NT-proBNP = N-terminal pro–B-type natriuretic peptide

31

P MRS = 31P cardiac magnetic

resonance spectroscopy

PCr = phosphocreatine RER = respiratory exchange

The therapeutic effects of perhexiline have been

the Declaration of Helsinki. The pre-defined

believed to relate to altered cardiac substrate utiliza-

primary endpoint was an increase in the car-

tion. Perhexiline has been shown to inhibit carnitine

diac PCr/ATP ratio with perhexiline therapy compared

palmitoyltransferase-1 and, to a lesser extent, carni-

with placebo. The secondary endpoints were im-

tine palmitoyltransferase-2 (8). These mitochondrial

provement in New York Heart Association (NYHA)

enzymes facilitate entry of medium- and long-chain

functional class, quality of life (Minnesota Living

fatty acids into mitochondria to undergo beta-

With Heart Failure Questionnaire [MLWHFQ]), and

oxidation

ratio

adenosine

left ventricular ejection fraction (LVEF). In a subgroup

triphosphate (ATP). This inhibition of fatty acid

of 22 patients, cross-heart respiratory exchange ratio

metabolism may be expected to lead to a reciprocal

(RER) was measured to assess cardiac substrate utili-

increase in carbohydrate activation (via allosteric

zation. The study protocol and methodology have been

activation of the enzyme pyruvate dehydrogenase)

previously reported (14). The study was approved by

and thus an improvement in myocardial efficiency

the South Birmingham Research Ethics Committee

and phosphocreatine (PCr)/ATP ratio.

(06/Q2707/7) and the Medicines and Healthcare Prod-

31

and

subsequently

produce

P cardiac magnetic resonance spectroscopy ( 31P

MRS)

allows

203

Improvement in Cardiac Energetics by Perhexiline

noninvasive

quantification

of

the

ucts Regulatory Agency (21761/0003/001) and was registered with ClinicalTrials.gov (NCT00841139).

PCr/ATP ratio, which is an accepted measure of car-

PATIENT SELECTION. Patients (n ¼ 50) were consec-

diac energetic status. It has been shown that the

utively recruited from the Advanced HF Programme at

PCr/ATP ratio is reduced in the failing human heart

the University Hospitals Birmingham NHS Foundation

(9,10). Therefore, we sought to determine whether

Trust (Birmingham, England) and the University

the therapeutic benefit of perhexiline in HF is related

Hospitals of Wales NHS Trust (Cardiff, Wales) between

to an improved cardiac PCr/ATP ratio and whether

February 2008 and June 2011. All patients were

this is a consequence of altered cardiac substrate

receiving maximal tolerated doses of evidence-based

utilization. Effective therapy for HF that does not act

HF

in the first instance by direct effects on cardiac

hibitors, beta-blockers, and mineralocorticoid recep-

metabolism may nevertheless in the longer term

tor antagonists). Inclusion criteria were nonischemic

result in improvements in the cardiac PCr/ATP ratio

dilated cardiomyopathy, symptoms of HF despite

via an improvement in HF syndrome, leading in turn

optimal tolerated medical therapy, and LVEF 70 Hz for speckle tracking

F I G U R E 1 The CONSORT Flow Diagram

A total of 1,637 patients were screened for inclusion, 278 met the inclusion criteria, and 50 were randomized. One patient was lost to follow-up. Twenty-two patients in each group underwent cardiac resonance spectroscopy; SNR ¼ signal-to-noise ratio.

31

P MRS. CONSORT ¼ Consolidated Standards of Reporting Trials; MRS ¼ magnetic

205

206

Beadle et al.

JACC: HEART FAILURE VOL. 3, NO. 3, 2015 MARCH 2015:202–11

Improvement in Cardiac Energetics by Perhexiline

echocardiography. Analysis was performed offline

T A B L E 1 Clinical Characteristics of the Patient Groups

Age, yrs

using commercially available software (GE Vingmed

Perhexiline Group

Placebo Group

p Value

62  1.8

60  2.43

0.49

Ultrasound, Horten, Norway). Peak systolic velocities, strain, strain rate, rotation, and twist were measured for each myocardial segment in triplicate and aver-

Male

22 (88)

16 (64)

0.10

Body mass index, kg/m2

27  1.1

29  0.9

0.23

Body surface area, m2

1.9  0.04

1.9  0.04

0.88

Heart rate, beats/min

70  2.92

69  3.10

0.92

Systolic blood pressure, mm Hg

120 [35]

120 [34]

0.59

Diastolic blood pressure, mm Hg

60 [20]

60 [10]

0.72

either the right internal jugular vein or right femoral

aged for global estimates. C r o s s - h e a r t s a m p l i n g . A coronary sinus thermodilution catheter was inserted via a 7-F sheath placed in

4

2

0.38

vein under local anesthesia. The catheter was guided

Loop diuretics

16

20

0.21

into place using fluoroscopy and small injections of

ACE-I/ARBs

25

25

—

radio-opaque contrast when required to confirm the

Beta-blockers

21

19

0.48

position of the catheter. This catheter was used to

Calcium channel blockers

0

1

0.31

take venous blood samples from the coronary sinus as

14

13

0.78

Digoxin

7

4

0.31

well as to measure flow by thermodilution. Arterial

Statins

13

9

0.24

Week 1

0.17  0.04

0

—

been taken. Samples were spun immediately in

Week 4

0.33  0.06

0

—

ethylenediaminetetraacetic acid, and plasma was

1.16  0.08

1.38  0.07

0.04

frozen in liquid nitrogen and stored at 80 C. These

Diabetes

Spironolactone

sheath. No heparin was used until these samples had

Serum perhexiline level, mg/l

PCr/gATP ratio NYHA functional class (class)

samples were taken simultaneously from an arterial

11 (II), 9 (III), 5 (IV) 14 (II), 10 (III), 1 (IV) 0.21

MLWHFQ score LVEF, % NT-proBNP level, pg/ml

25 [34]

36 [48]

0.79

27  1.44

30  1.34

0.21

620 [2,342]

241 [508]

0.02

samples were analyzed in a single batch at the end of the study for glucose, lactate, NEFA, and pyruvate. Blood samples for oxygen were taken in blood gas syringes, and measurement of oxygen was performed

Values are mean  SD, n (%), or median [interquartile range].

using a Bayer Rapidlab 800 series blood gas analyzer

ACE-I/ARBs ¼ angiotensin-converting enzyme inhibitors/angiotensin receptor blockers; ATP ¼ adenosine triphosphate; LVEF ¼ left ventricular ejection fraction; MLWHFQ ¼ Minnesota Living With Heart Failure Questionnaire; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; NYHA ¼ New York Heart Association; PCr ¼ phosphocreatine.

(Bayer Healthcare LLC, East Walpole, Massachusetts). Measurement of carbon dioxide was performed off site with isotope-ratio mass spectrometry using a Thermo Finnigan Delta XP isotope ratio mass spectrometer (Thermo Fisher Scientific UK, Loughborough, United Kingdom). S t a t i s t i c a l a n a l y s i s . Variables are expressed as

F I G U R E 2 Monitoring of Perhexiline Levels

mean  SD when normally distributed or median and interquartile range when not normally distributed. Continuous variables were compared between baseline data for perhexiline and placebo using unpaired Student t test (2-tailed) if variables were normally distributed and the Mann-Whitney U test if the data were non-normally distributed. The KolmogorovSmirnov test and normality plots were used to assess normality of continuous variables. Categorical variables were compared with the Pearson chisquare test. NYHA functional class was analyzed between groups using Kendall tau-b test. A 2-way repeated-measures analysis of variance was used for others to compare the effect of the intervention between the 2 groups. For non-normally distributed variables that failed normality testing with log transformation, the changes between groups were

Perhexiline levels were measured in all patients at the end of the first week and again at

compared by an unpaired Student t test (2-tailed) or

the conclusion of the intervention period. The dose of perhexiline was adjusted according

Mann-Whitney U test as appropriate. Correlations

to the level in the first week.

were performed with a bivariate Pearson r test. A p value of 0.05 was considered to indicate statistical

Beadle et al.

JACC: HEART FAILURE VOL. 3, NO. 3, 2015 MARCH 2015:202–11

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Improvement in Cardiac Energetics by Perhexiline

significance. The p values were not corrected for multiple comparisons. Statistical analyses were per-

F I G U R E 3 Relationship Between PCr/ATP Ratio and NYHA Functional Class

formed using IBM SPSS version 20 (IBM, Portsmouth, United Kingdom). SAMPLE SIZE. The primary endpoint was the change

in the PCr/ATP ratio after 4 weeks of treatment. Pilot work from our group using the same

31

P MRS tech-

nique with perhexiline revealed an improvement of 0.4 in the PCr/ATP ratio in the treatment group by comparing means. The response was normally distributed with an SD of 0.5. Using these data, 26 subjects in each arm provided at least 80% power for detecting a change of 0.4 in the PCr/ATP ratio.

RESULTS STUDY POPULATION. Fifty patients were random-

ized, of whom 47 were included in the analysis (Figure 1). One patient from the perhexiline group was lost to follow-up due to a hospital admission with intercurrent pneumonia at the time of follow-up. One

The cardiac 31P MRS PCr/ATP ratio was markedly lower in those patients with higher NYHA

patient in the placebo group withdrew from the study

functional class. ATP ¼ adenosine triphosphate; NYHA ¼ New York Heart Association;

after randomization but before starting an interven-

PCr ¼ phosphocreatine; other abbreviation as in Figure 1.

tion. Another patient in the placebo group withdrew due to adverse effects (headaches and lethargy). The baseline clinical characteristics of the 2 groups are

change in the placebo group (1.36  0.31 to 1.34  0.31;

shown in Table 1. The groups were matched for age,

p ¼ 0.37) (p < 0.001; 2-way repeated-measures anal-

sex, NYHA functional class, MLWHFQ scores, and

ysis of variance) (Table 2, Figure 4). The

conventional medical therapy. The PCr/ATP ratio was

spectra of a patient before and after the intervention

lower at baseline in the perhexiline group (1.16  0.08

are shown in Figure 5. The mean CRLBs for PCr and

vs. 1.38  0.07; p ¼ 0.036) and the NT-proBNP level

ATP for the entire group were 10.7% and 12.7%,

was higher (620 [2,342] pg/ml vs. 241 [508] pg/ml).

respectively, indicating a satisfactory signal-to-noise

31

P MRS

The mean serum perhexiline level at the end of

ratio (20). Three patients were excluded from the

study in the perhexiline arm was 0.33  0.3 mg/l, with

initial analysis because of a poor signal-to-noise ratio

2 patients (8.3%) falling below the lower threshold of

(CRLBs >20%).

the therapeutic range (0.15 mg/ml) (Figure 2). There were no significant differences in venous metabolites and insulin levels between the perhexiline and placebo groups.

SYMPTOMS. At follow-up, there was an improvement

in NHYA functional class in the perhexiline group compared with the placebo group (p ¼ 0.036). Thirteen patients in the perhexiline group improved by

MYOCARDIAL ENERGETICS. At baseline, the PCr/ATP

ratio correlated negatively with the MLWHFQ score (r ¼ 0.361, p < 0.05). There was a significant difference in mean PCr/ATP ratio between patients in

T A B L E 2 Effect of Perhexiline and Placebo

lower and higher NYHA functional classes (NYHA functional class II mean PCr/ATP ratio: 1.47  0.05;

Perhexiline Group

Placebo Group

Before Treatment

After Treatment

Before Treatment

PCr/gATP ratio

1.16  0.39

1.51  0.51

1.36  0.31

significant correlation between the PCr/ATP ratio

NHYA functional class, (class)

11 (II), 9 (III), 5 (IV)

2 (I), 16 (II), 14 (II), 10 (III), 15 (II), 8 (III) 3 (III), 3 (IV) 1 (IV)

and LVEF (r ¼ 0.1, p ¼ 0.52) or NT-proBNP (r ¼ 0.01,

MLWHFQ score

p ¼ 0.99) levels.

NT-proBNP level, pg/ml

NYHA functional class III and IV mean PCr/ATP ratio: 1.06  0.07; p ¼ 0.0005) (Figure 3). There was no

At

follow-up,

the

myocardial

PCr/ATP

ratio

increased by 30% versus baseline in the perhexiline group (1.16  0.39 to 1.51  0.51; p < 0.001) but did not

Parameter

p Value

1.34  0.31